I was walking down the corridor when one of the Medical Registrars walked passed looking perplexed, we said hello and passed on by, then he called after me “oh can I ask your opinion on…” A standard start to many a query for a Microbiologist! But this question was different, he was reading around the subject of endocarditis and was frustrated by the “guidelines” put out there by the expert bodies… he went on “their advice is sometimes different and even contradictory! How do you know what to follow?”

I agreed, which didn’t seem to satisfy him at all. So let me explain further in this blog, as it will take longer than a passing corridor conversation, unless you have the old Victorian corridors still, I may be able to explain it in the time it takes to walk one of those, ah the days when we all got more exercise at work.

Anyhow back to guidelines…There are numerous guidelines available to help guide therapy of infective endocarditis be it from Britain, America and Europe1,2,3 and mostly the guidelines are similar, however there is one significant difference in the treatment of infective endocarditis caused by Enterococcus spp.

The American Heart Association (AHA) and European Society for Cardiology (ESC) guidelines recommend using Ampicillin PLUS Ceftriaxone (AMP+CRO) as an alternative to Ampicillin PLUS Gentamicin (AMP+GENT) for Enterococcus faecalis infective endocarditis, whereas the British guideline does not recommend AMP+CRO and sticks to AMP+GENT or AMP alone. Working in a British hospital, we are obliged to use the British guidelines… “but, are the British correct asked the Med Reg?” Good question and it comes down to evidence and its interpretation. “But…” the Med Reg went on…”if the evidence available to all of the guideline committees is the same why are the interpretations and recommendations different!?!” “Another good question”, I said!

What is the problem with using AMP+CRO?

FACT: The cephalosporins available in the UK have no activity against Enterococcus spp. because they do not bind to the Penicillin Binding Proteins (PBP) that are involved in cell wall synthesis in this bacterium.Guideline suggestion: the combination of AMP+CRO may be more effective than AMP alone or AMP in combination with other antibiotics such as GENT. The theory being that the combination of AMP+CRO would saturate all of the different PBPs in E. faecalis and hence have a much greater effect than AMP alone.

Enterococcus faecalis has four PBPs (2, 3, 4 and 5). PBP4 and PBP5 are essential for the bacterium to produce its cell wall (required for its replication), therefore the more PBPs that are “bound” or blocked by an antibiotic, the more active that antibiotic is. AMP binds primarily to PBP4 and PBP5 but it also binds to the non-essential PBP2 and PBP3. Therefore some of AMPs activity is “wasted” on non-essential PBPs. So…if another molecule were to block PBP2 and PBP3 (even if this molecule has no actual antibiotic effect) then more of the AMP would be available to act on PBP4 and PBP5.

Ceftriaxone could be used as such a molecule as it does not bind to PBP4 and PBP5 and so has no activity on its own against E. faecalis but would theoretically make the AMP more effective. That’s the theory anyway… I sound sceptical because it would mean:

CRO would have to out-compete AMP for PBP2 and PBP3

There would have to be significant enough amount of AMP “left over” to have this increased effect on PBP4 and PBP5

This theory is behind the recommendations of the European and American guidelines which suggest the combination of AMP+CRO for the treatment of E. faecalis infective endocarditis.

I know, my tone suggests I’m not convinced! I believe that in order to assess the validity of the recommendation in any guidelines it is necessary to look at the original papers and not just take the guideline authors word for their recommendations.

So what evidence is presented in the ESC and AHA guidelines to support the use of AMP+CRO?The ESC and AHA guidelines cite 3 journal articles from Spain as evidence, however these articles share authors! Two of the articles share 6 authors and the other shares 2 authors. I feel this begs the question “are these really separate articles confirming the original studies or are they actually the same studies being presented later in time albeit with additional patients included?” It’s difficult to tell but there is at least a statement in one of the later articles that confirms that patients from the earlier study are included in the later study which in my opinion means that the later study is just an expansion of the earlier study and therefore should be considered to be a single piece of work. In this case these guidelines are actually only based on evidence from two journal articles, which are linked by common authors. Both journal articles are retrospective, non-randomised, cohort studies.

The panel of experts on the ESC guidelines also contains two of the authors of the original paper promoting the use of AMP+CRO. One of these authors declares in the original paper a conflict of interest; they received payment from Roche (who make Ceftriaxone) yet this conflict of interest does not appear in the guidelines conflict of interest declaration; however the ESC guideline conflict of interest declaration is a staggering 35 pages long! (The full guideline is only 41 pages long without the references!!... but at least it is free to access.) Many of the authors have received payment from diverse pharmaceutical companies and I can’t help but be concerned about potential bias when I read declarations like this.

The AHA guideline is better where potential conflicts of interest are concerned; a few members have been paid by pharmaceutical companies but the vast majority have not. I think the risk of bias is much less in this case.

So here goes, my opinion of these two papers (referenced 4 and 5 below):

The study by Pericas et al4 makes some dramatic general statements which to my reading are scientifically flawed. They state that “no randomised trials have provided high-quality data on alternatives to the classic combination of ampicillin plus aminoglycoside”. The authors also state that “the most important advance in the last two decades has been the proven efficacy and safety profile of ampicillin plus ceftriaxone”, but this is their own earlier small study. The authors say that “evidence from prospective studies comparing these two combinations [AMP+CRO versus AMP+GENT] is limited”; this is a gross understatement in that there are no prospective studies comparing them.

The study concludes that:

There is no difference in cure or treatment failure between patients treated with AMP+CRO and AMP+GENT

Renal failure is more common in patients treated with AMP+GENT

I believe the Pericas et al study is scientifically flawed for a number of reasons:

They have compared two groups of patients who are not comparable; the majority of patients in one treatment group are from 1997-2001 (47%) whereas the majority of patients in the other group are from 2006-2011 (70%). Medicine has changed a lot over this time and the supportive care that is available for patients has changed dramatically. Any difference in outcome for these 2 groups of patients could easily be due to differences in historical levels of care. There is evidence within the paper that this is actually the case.

The different regimens used over time show that there has already been a treatment selection bias over the period where there has been a change to using AMP+CRO in the later period because it is already believed to be better; an observation supported by the decision in later patient groups to switch patients from AMP+GENT to AMP+CRO with no comment as to why this was done.

There is no indication of how endocarditis has been diagnosed in the patients or how this might have changed over time. There is a comment of patients being excluded from analysis because of mixed infections… I have never seen a mixture of bacteria causing infective endocarditis and I don’t believe any of the guidelines consider this diagnosis, which calls in to question the diagnostic accuracy of the “cases” included in the study.

The regimen referred to as being used historically based on the AHA and ESC guidelines is incorrect. The authors state that the Gentamicin dose used was 3mg/kg 24 hourly whereas the guidelines actually say 3mg/kg 24 hourly in 3 equal divided doses i.e. 1mg/kg TDS. It is hoped that this is just a typographical error but if not the patients treated historically were treated incorrectly with a potentially more nephrotoxic regimen containing a single daily bolus of Gentamicin. There is also no evidence about monitoring of Gentamicin levels or use of other nephrotoxic drugs which might explain changes in renal function during treatment.

The mortality in this study was 23-27% regardless of which antibiotic regimen the patients received; this is considerably higher than the internationally reported mortality of 11% for the same disease based on 107 cases reported in 20056.

If AMP+CRO with modern care is the same as AMP+GENT with old fashioned care then it might well be the case that AMP+GENT with modern care is actually better than AMP+CRO with modern care. Could someone please do the direct comparative study!?

The N. Fernandez-Hidalgo et al. study5 is a bit better than the previously mentioned study and doesn’t make the bold unsupported claims that the other authors make.

The study concludes that:

AMP+CRO is as effective as AMP+GENT

There is virtually no risk of renal failure in patients treated with AMP+CRO

However, I still have some major concerns about this study.

The antibiotic regimens used to treat the AMP+GENT group are not standardised and are not all internationally accepted regimens for infective endocarditis. Once daily Gentamicin was used in 43% of the patients, which is not the accepted BD or TDS regimens, and could be associated with toxicity. Gentamicin was stopped before the end of treatment in 39% of the patients, which is also not standard practice.

The paper states that Gentamicin monitoring was not available in some of the hospitals using Gentamicin. Gentamicin levels were not monitored in 40% of the patients given Gentamicin and therefore it is unknown whether any of these patients had toxic levels. Not monitoring Gentamicin levels is very poor medical practice and should not be accepted in any hospital; if you can’t measure aminoglycoside levels you shouldn’t use them.

More patients were treated with AMP+CRO than AMP+GENT which suggests a selection bias towards AMP+CRO and could therefore influence the interpretation of the results towards a favourable outcome for AMP+CRO.

Whilst renal failure was more common in the AMP+GENT group compared to the AMP+CRO group this was not statistically significant (46% vs. 33%), however the antibiotic (Gentamicin) was blamed for the renal failure and therefore stopped more often in the AMP+GENT group (23% vs. 0%). This suggests that the physicians looking after the patients were likely to blame the Gentamicin for the renal failure even though it happened in both groups. To say that the Gentamicin caused renal failure is not supported by the evidence and is likely to be a perception bias on behalf of the physician looking after the patient. The study is wrong to suggest that there is virtually no risk of renal failure in patients treated with AMP+CRO… 33% of these patients had renal failure; they just didn’t blame the antibiotic.

Different hospitals tended to use different regimens therefore one hospital might use AMP+GENT whilst another might use AMP+CRO. Therefore there is the possible complication that the standard of supportive care might be different in each hospital which might explain any differences in outcome apart from the antibiotics.

An important conclusion that is briefly mentioned in the text, but for which no data is made available, is that in the subset analysis of high level Gentamicin sensitive strains of Enterococcus faecalis the rate of septic perivalvular complications was statistically much higher in the AMP+CRO group (40% vs. 26%). Why is the data not shown? It makes me question what other differences are not shown?

The mortality in this study was 21-22% regardless of which antibiotic regimen was given; this is considerably higher than the internationally reported mortality of 11% for the same disease based on 107 cases reported in 20056.

Summary of the evidence – my opinion

The evidence in support of using AMP+CRO to treat E. faecalis infective endocarditis is not of sufficient quality to allow a recommendation to use this treatment routinely

No study directly compares AMP+CRO against AMP+GENT or AMP alone

Renal failure MAY be more common with AMP+GENT than AMP+CRO, especially if antibiotic levels are not monitored

Valvular complications ARE more common in patients treated with AMP+CRO than AMP+GENT

If using Gentamicin then the correct dose must be used and antibiotic levels must be monitored and doses adjusted accordingly

Cephalosporins are known to increase C. difficile infection and ESBL-producing microorganisms

What do the British guidelines say?The British guidelines do consider the question of AMP+CRO and this is their conclusion1:“There has been anecdotal success treating high-level aminoglycoside-resistant (HLAR) Enterococcal endocarditis with penicillin and ceftriaxone combinations. However, in a nonrandomized open-label multicentre evaluation of this combination, an in-hospital mortality rate of 23% was reported, which is much higher than the 11% seen in international studies. Given the lack of evidence that such penicillin with cephalosporin combination therapy is superior to monotherapy with penicillin, the current UK epidemic of C. difficile infection and increasing concerns about ESBL-producing microorganisms, the Working Party does not recommend the routine addition of ceftriaxone to a penicillin for HLAR enterococci.”

So what is my practice?I follow the British guidelines which recommend using AMP+GENT for E. faecalis infective endocarditis when the organism has been shown to be sensitive to high-level Gentamicin and to use AMP on its own when it is resistant to high-level Gentamicin, and continue the therapy for ≥ 6weeks when using AMP on its own. In the meantime I think AMP+CRO may be fool’s gold, it may appear to be a gleaming treatment option but like pyrite its metallic lustre and colour only superficially resembles gold, closer examination reveals it is not the true article. I’ll wait and see if someone can produce high quality evidence that can convince me to change my practice. Beware of bias in scientific research and if you wish to claim something as “your area of interest” always evaluate the source evidence objectively rather than relying on the guideline’s synopsis.

Fool's gold

References

Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. K Gould et al. J Antimicrob Chemo 2012; 67: 269-289